Journal of Surgical Research 171, e33–e45 (2011)doi:10.1016/j.jss.2011.07.008

Meta-Analysis of Trials Comparing Minimally-Invasive and Open Liver

Resections for Hepatocellular Carcinoma

Alessandro Fancellu, M.D.,*,1 Alan S. Rosman, M.D., F.A.C.P.,† Valeria Sanna, M.D.,‡ Giuseppe R. Nigri, M.D.,§Luigi Zorcolo, M.D.,k Michele Pisano, M.D.,{ and Marcovalerio Melis, M.D.#

*Department of Surgery-Institute of Clinica Chirurgica, University of Sassari, SS, Italy; †Section of Gastroenterology and MedicineProgram,Mount Sinai School of Medicine and Bronx VAMC, NewYork, NewYork; ‡Department of Oncology, ASL n.1 Sassari, SS, Italy;§Department of Surgery, St. Andrea Hospital, Sapienza University of Rome, RM, Italy; kDepartment of Surgery, University of Cagliari,CA, Italy; {Department of Surgery, Ospedali Riuniti di Bergamo, BG, Italy; and #Division of Surgical Oncology, New York University

School of Medicine, NY Harbor Healthcare System VAMC, New York, New York

Originally submitted March 27, 2011; accepted for publication July 7, 2011

Background. Recent literature suggests thatminimally-invasive hepatectomy (MIH) for hepatocel-lular carcinoma (HCC) is associated with better perio-perative results and similar oncologic outcomescompared to open hepatectomy (OH). However, previ-ous reports have been limited by small sample sizeand single-institution design.Methods. To overcome these limitations, we per-

formed a meta-analysis of studies comparing MIHand OH in patients with HCC using a random-effectsmodel.Results. Nine eligible studies were identified that

included 227 patients undergoing MIH and 363 under-goingOH. Patients were similar respect to age, gender,rates of cirrhosis, hepatitis C infection, tumour size,and American Society of Anesthesiology classification.TheMIHgrouphad lower rates of hepatitis B infection.There were no differences in type of resection (ana-tomic or non-anatomic), use of Pringle’s maneuver,and operative time. Patients undergoing MIH hadless blood loss [differenceL217 mL; 95% confidence in-terval (CI), –314 to L121], lower rates of transfusion[odds ratio (OR), 0.38; 95%CI, 0.24 to 0.59], shorter post-operative stay (difference L5 days; 95% CI, –7.84to L2.25), lower rates of positive margins (OR, 0.30;95% CI, 0.12 to 0.69) and perioperative complications(OR, 0.45; 95% CI, 0.31 to 0.66). Survival outcomeswere similar in the two groups.Conclusions. Although patient selectionmight have

influenced some of the observed outcomes, MIH was

1 To whom correspondence and reprint requests should be ad-dressed at Department of Surgery-Institute of Clinica Chirurgica,University of Sassari, V.le San Pietro, 43, 07100 Sassari, Italy.E-mail: afancel@uniss.it.

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associated with decreased blood loss, transfusions,rates of positive resectionmargins, overall and specificmorbidity, and hospital stay. Survival outcomes didnot differ betweenMIHandOH, although further stud-ies are needed to evaluate the impact of MIH on long-term results. � 2011 Elsevier Inc. All rights reserved.

Key Words: hepatocellular carcinoma; minimallyinvasive; laparoscopy; open hepatectomy.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most commonprimary liver cancer and one of the most common ma-lignancies in the world, accounting for approximatelyone million deaths per year [1]. Curative options forHCC include resection and liver transplantation. Per-cutaneous ablative techniques are accepted as anattractive alternative to surgery in patients withsmall-size HCC; however, large studies suggest thatresection is associated with lower tumor recurrenceand better survival [2–5]. Open hepatectomy (OH)has traditionally been the primary treatment for re-sectable HCC in patients with preserved liver functionor well compensated cirrhosis who are not transplantcandidates [5–7].

In recent years, advances in minimally-invasive liverresection techniques have led to a surge in minimally-invasive hepatectomy (MIH) for HCC [8–10]. Benefitsof laparoscopic liver resection may include reducedpostoperative pain, decreased length of recovery, andlower complication rates [8–12]. However, most ofthe studies reporting on MIH are retrospective,

0022-4804/$36.00� 2011 Elsevier Inc. All rights reserved.

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single-institution case series of a relatively small num-ber of patients and included both metastatic and pri-mary liver neoplasms, thus resulting in limitedstatistical power for evaluation of outcomes after lapa-roscopic resection of HCC. In 2007 Simillis et al. per-formed a meta-analysis of studies comparing MIH andOH for benign and malignant neoplasms, however sur-vival items and outcomes specifically related to HCCtreatment were not addressed [10]. In 2009, an updatedmeta-analysis of studies comparing laparoscopic versusopen resection for benign and malignant tumors waspublished and reported on 1906 hepatic resectionsfrom twenty-six studies [13]. The authors concludedthat long-term survival for malignant tumors (thus in-cluding HCC, metastases, and other primaries) is com-parable in the two groups and that the use oflaparoscopic hepatic resection for benign and malig-nant tumors is a safe alternative to open hepatic resec-tion. However, a comparison between MIH and OHspecifically for HCC was not addressed and importantissues of surgical treatment of HCC, such as coexis-tence of cirrhosis, tumor size, and extension of hepaticresection were unexamined. Moreover, since that timenew articles comparing MIH and OH for HCC havebeen added to the literature. We performed a meta-analysis of studies comparing MIH and OH specificallyfor HCC.

MATERIALS AND METHODS

Study Selection

A systematic literature search was performed using Embase, Med-line, Cochrane, and PubMed databases, for studies comparing MIHto conventional OH, by using the following keywords: ‘‘minimally-invasive’’ or ‘‘laparoscopic’’ or ‘‘laparoscopy’’ and ‘‘hepatocellular carci-noma’’ or ‘‘hepatic resection.’’ The ‘‘related articles’’ function was usedto broaden the search and all abstracts, studies, and citations scannedwere reviewed as well as the references of relevant articles. The latestdate for this search was October 31, 2010. No language restrictionswere made.

Inclusion Criteria

To be included in this meta-analysis, studies had to: (1) compareMIH (pure laparoscopic or hand-assisted laparoscopy) and OH in pa-tients undergoing resection forHCC; (2) include at least 10 patients ineach group; (3) report on at least one of the outcomes of interest men-tioned below; (4) contain a previously unreported patient group. If pa-tient material was reported more than once by the same institution,the most informative and/or recent article was included in ouranalysis.

Exclusion Criteria

We excluded from our meta-analysis: (1) trials comparingminimally-invasive and open resection for ‘‘hepatic neoplasms’’ inwhich it was impossible to extract the data specifically related toHCC patients; (2) studies in which the outcomes of interest (specified

below) were not reported or impossible to calculate for bothminimallyinvasive and open techniques.

Data Extraction

Two reviewers independently identified the potentially rele-vant articles and extracted the following data: first author, year ofpublication, study population characteristics, study design, numberof subjects operated on with each technique, conversion rate fromminimally invasive to open technique, tumor characteristics, opera-tion related factors, perioperative outcomes, disease-free and overallsurvival. In few instances data not originally reported in the studywas obtained directly from the authors.

Outcomes of Interest and Definitions

For the purposes of this study, we defined anatomic resections thosehepatectomies guided by the intra-hepatic anatomy as described byCouinaud (e.g., removal of one or more segments) [14], and non-anatomic resection those minor hepatectomies involving less thanone segment (e.g., wedge resections).

All the studies were abstracted for the following relevant data:

- Patients baseline characteristics: age, gender, rates of hepatitisB and C infection, ASA (American Society of Anesthesiology)score, rates of cirrhosis, and tumor size.

- Operation-related outcomes: extent of resection (number of seg-ments removed, anatomic resections versus non-anatomic resec-tion), conversion rate, operative time, need and duration forPringle maneuver, blood loss, rates of transfusion, status of re-section margins (positive versus negative), width of resectionmargins.

- Duration of postoperative hospital stay.- Postoperative complications: mortality, overall and specificmorbidity.

- Duration of follow-up and long-term outcomes including disease-free and overall survival.

Statistical Analysis

Meta-analysis was performed in line with recommendations fromthe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. Variables were pooled only ifevaluated by three or more studies. Both qualitative and quantitativedata were pooled using a random-effects model. The rates of conver-sion from a laparoscopic to an open procedure were pooled using theinverse of the variance of the rates [16, 17]. The 95% confidence inter-vals for rates were calculated using standard statistical methods [18].In dealing with rates equal to zero, an alternate method described byHanley and Lippman-Hand [19] was used. For data derived from con-tingency tables (e.g., complication rates for laparoscopic and open pro-cedures), we computed the odds ratio (OR) and 95% confidenceinterval (CI) [20]. In cases of unstable estimators (which occur if therate of an event is either 0 or 1), 0.5 was added to all the cells to esti-mate the odds ratio [18, 21]. An odds ratio significantly less than 1 fa-vored laparoscopic surgery, whereas an odds ratio significantlygreater than 1 favored the open procedure. For continuous variables(e.g., length of operation, days of hospital stay), we calculated the dif-ference in mean values between the two procedures and its 95% con-fidence interval [20]. This method requires that the study report thestandard errors of the mean, the standard deviations, or the confi-dence intervals. Thus, studies that did not report any of these param-eters were not included in the statistical pooling of continuousvariables. The outcome variables (e.g., rates, odds ratios, and differ-ence in mean values) were pooled using a random-effects model ac-cording to the method of Der Simonian and Laird [22], as furtherdescribed by Fleiss [21]. We tested for homogeneity using the

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random-effects model to calculate the Q statistic and associated pvalue [20]. The outcome values (either odds ratios or difference inmeans) and their 95% confidence intervals are reported. All P values<0.05 (two-tailed) were considered significant. Funnel plots were con-structed as described by Peters et al. [23] in order to assess for publi-cation bias. For qualitative outcomes, precision (as defined by theinverse of the standard error of the odds ratio) was plotted againstthe odds ratio on a logarithmic scale. For quantitative variables, thepooled difference in outcomes between laparoscopic and open surgerywas used for the x-axis. A broken vertical line was also plotted to indi-cate the pooled odds ratio or difference in outcome. The lack of studieswith negative outcomes and lowprecisionwould produce an asymmet-ric plot and suggest a publication bias.

FIG. 1. Selection of article

RESULTS

Included Studies

The PRISMA flow diagram for systematic reviewis presented in Figure 1. Nine studies comparingMIH and OH for patients with a solitary HCC, pub-lished between January 2001 and October 2010,were considered suitable for the meta-analysis [6,25–32]. On review of the data extraction, there was100% agreement between the two reviewers. Three

s for meta-analysis [12, 24].

TABLE 1

Characteristics of Studies Included in the Meta-analysis

Author/year of publication Study designNo. of patientsundergoing MIH

No. of patientsundergoing OH

Selection criteriafor MIH Main authors’ conclusions

Aldrighetti et al. [30], 2010 Prospective (MIH) matchedretrospective (OH)

16 16 HCC < 12 cm in diameter,located in the Couinaudsegments 2 to 6

MIH feasible and safe inselected patients withHCC, with good surgicalresults and similaroutcomes in terms of OSand DFS

Tranchart et al. [32], 2010 Prospective (MIH) matchedretrospective (OH)

42 42 Compensated cirrhosis ornoncirrhotic liver,esophageal varices grade�1, PLT count � 80 x 109/l,tumors well clear from theportal pedicle or hepaticveins, ASA score � 3

Better postoperative outcomewithout oncologicconsequences in selectedpatients undergoing MIH

Endo et al. [31], 2009 Retrospective 10 11 HCC < 5 cm in diameter,located in The Couinaudsegments 2 or 3

MIH in LLH superior to OHin terms of short-termsresults withoutdeterioration of long-termsurvival. MIH alternativechoice for treatment ofHCC

Belli et al. [29], 2009 Retrospective 54 125 Well compensated cirrhosis(Child-Pugh class A/B lowgrade) without signs ofsevere portalhypertension, PLT count�80 x 109/l, exophytic orsubcapsular tumor < 5 cmin diameter located in theCouinaud segments 2 to 6

MIH in cirrhotic liver feasibleand safe in selectedpatients with adequatelong-term survival andrecurrence when stratifiedfor tumor characteristicsrelated to survival outcome

Sarpel et al. [28], 2009 Retrospective matched 20 56 n/r MIH and OH no significantlydifferent in terms ofmargin status, recurrence,or survival; MIHreasonable alternative toOH in selected cases

Lai et al. [27], 2009 Prospective (MIH) matchedretrospective (OH)

25 33 Normal livers or Child class Acirrhosis, HCC < 5 cm indiameter, located in theCouinaud segments 2 to 6

MIH for HCC feasible andsafe in selected patients;midterms survivalfavorable; shorter hospitalstay; importance of expertsurgical team

Kaneko et al. [25], 2005 Prospective (MIH) matchedretrospective (OH)

30 28 HCC < 6 cm in diameter,solid, located in theCouinaud segments 2 to 6

MIH beneficial for patientquality of life without somedisadvantages of OH inselected patients

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Laurent et al. [6], 2003 Prospective (MIH) matchedretrospective (OH)

13 14 Subcapsular HCC < 5 cm indiameter, located in theCouinaud segments 2 to 6

Rate of decompensation ofliver disease lower afterMIH for subcapsular HCCcomplicating chronic liverdisease

Shimada et al. [26], 2001 Retrospective matched 17 38 Small, well demarcated andperipheral HCC located inthe Couinaud segments 2to 6

Better short-term outcomefor MIH; long-termprognosis similar; MIHalternative for treatmentof selected cirrhoticpatients

MIH ¼ minimally invasive hepatectomy; OH ¼ open hepatectomy; HCC ¼ hepatocellular carcinoma; OS ¼ overall survival; DFS ¼ disease-free survival; PLT ¼ platelet; ASA ¼American Society of Anesthesiology; LLH ¼ left lateral hepatectomy.

TABLE 2

Comparisons of Baseline Characteristics

Author

No. ofpatients

Mean age(y)

Proportionmale no. (%)

Hepatitis B carrierno. (%)

Hepatitis C carrierno. (%)

Proportion with chronicliver disease/cirrhosis no. (%)

Mean sizeof tumor(cm)

ASA score(mean)

MIH OH MIH OH MIH OH MIH OH MIH OH MIH OH MIH OH MIH OH

Aldrighetti 16 16 65 71 11 (68.7) 12 (75.0) n/r n/r n/r n/r 9 (56.2) 9 (56.2) 4.00 4.6 2.12 2.50Endo 10 11 72 64 8 (80.0) 8 (72.7) 2 (20.0) 3 (27.3) 8 (80.0) 5 (45.4) 6 (60.0) 9 (81.8) 3.00 4.1 n/r n/rTranchart 42 42 63 65 27 (64.3) 28 (66.7) n/r n/r n/r n/r 31 (73.8) 34 (80.9) 3.58 3.68 2.09 2.11Belli 54 125 63 61 31 (57.0) 78 (62.0) 2 (3.7) 16 (12.8) 50 (92.6) 102 (81.6) 54 (100) 125 (100) 3.80 6.00 1.87 1.84Sarpel 20 56 63 58 15 (75.0) 45 (80.0) n/r n/r n/r n/r 9 (45.0) 27 (48.2) 4.30 4.30 n/r n/rLai 25 33 59 59 18 (72.0) 21 (64.0) 23 (92.0) n/r 1 (4.0) n/r 23 (92.0) 31 (93.9) n/r n/r n/r n/rKaneko 30 28 59 61 18 (60.0) 18 (64.0) 4 (13.3) n/r 21 (70.0) n/r 13 (43.3) n/r 3.00 3.10 n/r n/rLaurent 13 14 62 65 10 (77.0) 10 (71.0) 4 (3.8) 6 (42.8) 5 (38.5) 5 (35.7) 13 (100) 14 (100) 3.35 3.43 n/r n/rShimada 17 38 62 63 15 (88.0) 24 (63.0) 2 (11.8) 7 (18.4) 12 (70.6) 24 (63.1) 13 (76.5) 28 (73.7) 2.60 2.50 n/r n/r

MIH ¼ minimally invasive hepatectomy; OH ¼ open hepatectomy; ASA ¼ American Society of Anesthesiology.

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studies were conducted in Japan, one in the USA,two in Italy, one in Hong Kong, and two in France.The reports were primarily retrospective studies ofcomparable patients. No randomized trials wereidentified. A total of 227 patients underwent MIHand 363 had OH. The characteristics of the studiesare summarized in Table 1.

Patient Characteristics

Baseline characteristics of the studies are summa-rized in Table 2. Patients in the two groups were sim-ilar with respect to age (63 versus 62 years; difference,0.44; 95% CI, –2.88 to 3.78), rates of male gender (0.67versus 0.67; OR, 0.93; 95% CI, 0.65 to 1.34), cirrhosis(0.80 versus 0.82; OR, 0.75; 95% CI, 0.45 to 1.22), ratesof hepatitis C infection (0.79 versus 0.72; OR, 1.87;95% CI, 0.86 to 4.05), ASA classification (averageASA score 1.99 versus 1,97; difference, –0.03; 95%CI, –0.36 to 0.30) and tumor size as measured by thepathologist (3.53 versus 4.53 cm; difference, –0.51cm; 95% CI, –1.20 to 0.18). The MIH group had lowerrates of hepatitis B infection than the OH group (0.10versus 0.17; OR 0.40; 95% CI, 0.21 to 0.76). The man-uscripts considered did not report specifically on de-gree of cirrhosis (i.e., Child class) and this data wasnot included in our analysis. Eight studies indicatedtumor characteristics required for laparoscopic ap-proach [6, 25–27, 29–31]. They included solitary HCCof maximum size of 5 [6, 26, 27, 29, 31], 6 cm [25] or12 cm [30], mostly located in the left (segments 2–4)or right anterior lateral segments (5 and 6). Only in

TABL

Comparisons of Perio

Variables No. of pooled studies Mean MIH

OperativeNon-anatomic resections 6 0.38Anatomic resections > 1 seg 5 0.37Anatomic resection ¼ 1 seg 6 0.23Pringle maneuver 4 0.10Operative time (min) 7 195Evaluated blood loss (ml) 6 361Patient transfused (%) 6 0.10Resection margin width (mm) 5 10.57Positive resection margins 5 0.09

PostoperativeMean hospital stay (days) 7 10.36Overall morbidity 9 0.15Liver failure 4 0.04Ascites 3 0.05Bile leak 4 0.02Postoperative hemorrhage 3 0.08Pulmonary complications 5 0.03Mortality 7 0.01

MIH ¼ minimally-invasive hepatectomy; OH ¼ open hepatectomy; se

two cases the lesions were located in the segments7 and 8 [25, 30]. In two studies MIH was consideredonly for subcapsular tumor location [6, 29]. One studywas restricted to left lateral lobectomies (segments2 and 3) [31].

Perioperative Outcomes (Table 3)

Operative Parameters

Eight studies specified the type of resection per-formed. Only three authors reported on laparoscopic re-sections including more than two segments [27, 29, 32].

There were no differences between MIH and OHgroups in type of resection performed (i.e., anatomicversus non-anatomic) (rates of non-anatomic resection0.38 versus 0.39; OR, 0.92; 95% CI, 0.55 to 1.55), usePringle’s maneuver (rates 0.10 in the MIH group and0.23 in theOHgroup;OR, 0.15; 95%CI, 0.01 to 2.08), op-erative time (195 versus 193min; difference, –2,22; 95%CI, –25.60 to 21.16) (Fig. 2A). The width of the resectionmargins was not significantly different (10.57 versus9.37 mm; difference, 0.54; 95% CI, –0.70 to 1.80). Therates of positive margins were lower for the MIH group(0.09 versus 0.18; OR 0.30; 95% CI, 0.12 to 0.69)(Fig. 2B). Patients undergoing MIH had significantlyless blood loss (361 mL versus 603 mL; difference,–217 mL; 95% CI, –314 to �121) (Fig. 2C) and requiredfewer transfusions (transfusion rates 0.10 versus 0.21;OR 0.38; 95% CI, 0.24 to 0.59) (Fig. 2D). The rates forconversion to an open procedure ranged from 0 to 0.15.The pooled rate was 0.04 (95% CI, 0.02 to 0.07).

E 3

perative Outcomes

Mean OH Difference or odds ratio 95% LL CI 95% UL CI

0.39 0.92 0.55 1.550.28 1.32 0.61 2.860.27 0.73 0.42 1.280.23 0.15 0.01 2.08

193 �2.22 �25.60 21.16603 �217 �314 �121

0.21 0.38 0.24 0.599.37 0.54 �0.70 1.800.18 0.30 0.12 0.69

13.62 �5.04 �7.84 �2.250.25 0.45 0.31 0.660.15 0.22 0.11 0.440.23 0.20 0.10 0.400.05 0.43 0.13 1.380.05 1.31 0.32 5.360.07 0.34 0.13 0.870.03 0.44 0.17 1.11

g ¼ segment; min ¼ minutes; mL ¼ milliliters; mm ¼ millimeters.

FIG. 2. Operative outcomes. (A)Meta-analysis of operative time. (B)Meta-analysis of positivemargins. (C)Meta-analysis of intraoperativeblood loss. (D) Meta-analysis of transfusion rates.

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Postoperative Course

Patients in the MIH group had a shorter postopera-tive stay (10.36 versus 13.62 days; difference, –5.04,95%CI, –7.84 to�2.25) (Fig. 3A) and fewer overall com-plications (0.15 versus 0.25; OR, 0.45; 95% CI, 0.31 to0.66) (Fig. 3B). Analysis of specific morbidity revealedthat rates of liver failure were decreased in MIH group(0.04 versus 0.15; OR, 0.22; 95% CI, 0.11 to 0.44)(Fig. 3C), as well as postoperative ascites (0.05 versus0.23; OR, 0.20; 95% CI, 0.10 to 0.40) and pulmonarycomplications (0.03 versus 0.07; OR, 0.34; 95% CI,0.13 to 0.87). There were no significant differences be-tween MIH and OH groups in postoperative hemor-rhage (0.08 versus 0.05; OR, 1.31; 95% CI, 0.32 to5.36) and bile leak (0.02 versus 0.05; OR, 0.43; 95%CI, 0.13 to 1.38). Thirty-day mortality was lower forMIH group but the difference just fell short of statisticalsignificance (OR, 0.44; 95% CI, 0.17 to 1.11) (Fig. 3D).

Assessment for Publication Bias

Funnel plots (shown in Figs. 4 and 5) were con-structed in order to assess for publication bias. Theplots for the outcomes operative time, positive margins,intraoperative blood loss, transfusion rates, hospitaldays, and postoperative liver failure (Fig. 4A–D,Fig. 5A and C) demonstrated some symmetry. In con-trast, the plots for overall morbidity and 30-daymortal-ity (Fig. 5B and D) suggested a decreased number ofpositive studies with low precision. This is generallynot seen with typical publication bias.

Survival (Table 4)

All studies compared oncologic results ofMIHandOH.Three-year overall survival rates were 0.72 and 0.64, re-spectively, for MIH and OH. Five-year overall survivalrate were 0.63 and 0.56, respectively, for MIH and OH.

FIG. 3. Postoperative outcomes. (A) Meta-analysis of hospital stay. (B) Meta-analysis of postoperative overall morbidity. (C) Meta-analysisof postoperative liver failure. (D) Meta-analysis of 30-d mortality.

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On the whole, no differences were found between MIHand OH in overall- and disease-free survival.

DISCUSSION

Development of laparoscopic approach for livermalig-nancies has been slow compared with the developmentof this procedure in other fields of surgical oncology.Wide acceptance of this technique has been delayed byconcerns regarding technical difficulties, risk of bleed-ing, air embolism, bile leakage, tumor seeding, andfear of oncologic inadequacy and tumor spread [6, 8,33, 34]. However, recent advances in laparoscopic tech-niques and instrumentshave led to a surge inminimallyinvasive approach for HCC. Several retrospective stud-ies and literature reviews have shown the safety andfeasibility of MIH for HCC [8, 9–12, 25–29, 33–35].

Furthermore, MIH seemed to be associated withfaster postoperative recovery and decreased morbidity

compared with OH [25–29, 35–37]. Still, most studieswere retrospective, single-institution series of a rela-tively small number of patients, thus resulting in lim-ited statistical power for evaluation of outcomes. Toovercome these limitations, we performed a meta-analysis comparing MIH and OH specifically for HCC.We have applied a rigorous statistical method to our lit-erature review, with amain aim of detecting significantdifferences in outcomes between open and minimallyinvasive liver resections.

Previous studies of MIH have identified a conversionrate of 5%–15%, with the most common causes beingbleeding and failure to progress secondary to difficultexposure [8, 9]. The relatively low pooled conversionrate of 4% of our meta-analysis is likely a reflectionof both surgeons’ expertise and selection bias; twostudies only considered for MIH patients with subcap-sular tumors. Moreover, the great part of MIH was car-ried out for HCC located in antero-lateral segments(segments 2 to 6, so-called ‘‘laparoscopic segments’’)

FIG. 4. Funnel plots of operative outcomes. (A) Funnel plot of operative time. (B) Funnel plot of positive margins. (C) Funnel plot of intra-operative blood loss. (D) Funnel plot of transfusion rates.

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[8, 38]. Subcapsular tumors located in these segmentsare particularly suited for laparoscopic approach be-cause of their accessibility to laparoscopic instrumentsand relative distance from major biliary and vascularstructures. Laparoscopic resections of HCC located inthe postero-superior segments have also been de-scribed [25, 39, 40], but their safety and oncologic ade-quacy might need further investigations.

Left lateral lobectomy is a particularly attractiveprocedure for a laparoscopic approach, due to the pe-ripheral location with minimal requirement for hilardissection and ease of controlling bleeding [9, 31, 41].Some degree of patient selection was likely present inthe studies included in our meta-analysis, as sug-gested by the fact that non-anatomic resections andleft lateral lobectomy (segment 2 and 3) were themost common types of hepatectomy performed. There-fore, the readers should be cautious when interpretingthe results of our review, which may not apply specifi-cally for extensive liver resections. On the other hand,our results do hold validity for most of liver resectionscurrently performed for HCC. In fact, since underlyingcirrhosis usually precludes major hepatectomies, pa-tients with centrally-located lesions are often treated

with ablative techniques, and hepatectomies largerthan bi-segmentectomies are rarely performed inHCC patients.

We found no significant difference in operative timebetweenMIH and OH groups, despite different authorsacknowledging longer operative times for MIH in thefirst part of their experience [25, 26, 29, 42].

Our meta-analysis demonstrated reduced blood lossand transfusion rates in the MIH group. This point isof particular interest, since intraoperative bleeding isone of the major concerns during laparoscopic liver re-sections in cirrhotic patients [8, 9, 26]. Remarkably,these results are in line with previous reviews andmeta-analysis showing decreased blood loss and needfor transfusion when laparoscopy is used for hepatic re-sections, [8–11, 36]. Limited blood loss during MIH canbe obtained by maintenance of a positive abdominalpressure during parenchymal transection, and by usingappropriate laparoscopic techniques (e.g., hand-assistance for parenchymal compression) and hemo-static devices (e.g., radio-frequency assisted resection)[25, 33, 36]. However, the difference in blood loss mighthave also been influenced by selection bias describedabove (i.e., more favorable anatomic location for MIH).

FIG. 5. Funnel plots of postoperative outcomes. (A) Funnel plot of hospital days. (B) Funnel plot of postoperative overallmorbidity. (C) Fun-nel plot of postoperative liver failure. (D) Funnel plot of 30-d mortality.

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Selective use of Pringle maneuver is suggested for lapa-roscopic approach instead of routine use, even in cir-rhotic patients [42].

In our analysis, the width of the resection margin be-tween MIH and OH was not significantly different.Clearance of surgical margins is one of the main con-cerns in laparoscopic surgery of liver malignancies,however themarginpositivitywasmeasureddifferentlyin the papers included in our meta-analysis. Laurentand Shimada reported respectively 47.3% and 14.8%of tumors invading within 5 mm of the surgical cut sur-face [6, 26]. Sarpel reported 22.4% of positive marginsdefined as tumor invading within 3 mm of the surgical

TABL

Comparisons of Overall an

Characteristic No. of pooled studies Mean MIH Mean

1 y OSS 8 0.94 0.92 r OSS 4 0.76 0.73 y OSS 7 0.72 0.65 y OSS 5 0.63 0.51 y DFS 8 0.83 0.82 y DFS 5 0.61 0.63 y DFS 7 0.50 0.55 y DFS 4 0.37 0.3

MIH ¼ minimally-invasive hepatectomy; OH ¼ open hepatectomy; O

cut surface [28]. In Belli’s experience, 4.5% of patientshad margins invaded by tumor (this data was used inour analysis) and 33.5% had resection margins lessthan 1 cm [29]. Despite different definitions, most au-thors found that rates of positive margins after MIHgroup were lower or similar to those after OH. Accord-ingly, in our meta-analysis, rate of positive marginswas found to be significantly lower for the MIH group.This finding could be explained by a more accurateand meticulous dissection during a laparoscopic ap-proach or, again, just be a result of a selection bias forwhich tumors with favorable location were selected forlaparoscopy. If further confirmed by other studies, this

E 4

d Disease-Free Survival

OH Difference or odds ratio 0.95LLCI 0.95 UL CI

1 1.32 0.63 2.804 1.02 0.60 1.744 1.24 0.79 1.926 1.47 0.83 2.610 1.20 0.74 1.962 0.84 0.55 1.293 0.86 0.60 1.248 1.14 0.63 2.05

SS ¼ overall survival; DFS ¼ disease-free survival.

FANCELLU ET AL.: META-ANALYSIS OF LIVER RESECTIONS FOR HCC e43

findingmay represent one of the strongest arguments infavor of laparoscopic approach for HCC resection.

Length of hospital stay was lower for MIH. Hospitalstay varied considerably across the studies includedin the meta-analysis, likely because of differences incultural and health systems across institutions fromdifferent continents [9].

The major advantages of MIH were manifest inanalysis of perioperative complications: overall mor-bidity was lower in patients undergoing minimally in-vasive surgery. This is not a novel finding, as previousreport comparing surgical outcomes after laparo-scopic and open liver surgery have consistently shownbetter results with the former approach [8–10, 43].Remarkably, our meta-analysis showed a lower rateof postoperative ascites and liver failure in the MIHgroup, maybe a result of decrease disruption of porto-systemic shunts with laparoscopy. Given the retro-spective nature of most of the studies included,patient selection (e.g., patients with higher degree ofcirrhosis undergoing open procedures) might havealso influenced those outcomes. The lower rates ofpostoperative ascites and liver failure may partiallyexplain the lower mortality rates seen after MIH, asliver failure is a leading cause of mortality after liverresection for HCC in cirrhotic patients [8]. Preser-vation of collaterals with lower increase of portal hy-pertension may decrease postoperative ascites anddigestive bleeding [44].

Other possible explanations for decreased morbidityin cirrhotic patients undergoing laparoscopic liver re-sectionmay include limitedmobilization andmanipula-tion of the liver, restricted fluid requirements anddecreased blood loss, with consequently reduced third-space accumulation and hyperaldosteronism [6, 10,12, 37, 45–48]. Another theoretical advantage of MIHis facilitation of eventual subsequent liver transplantbecause of the reduction in intra-abdominal adhesions[6, 9, 42, 49]. In our meta-analysis, 30-day mortalitywas lower for MIH but the difference just missed statis-tical significance.

Our review contributes to establish that in well se-lected patients MIH is a safe and effective procedure.However,MIHwill be accepted as a suitable alternativeto OH in patients with HCC only if oncologic outcomeswill be proven to be at least equal. In ourmeta-analysis,almost all studies reported similar survival and DFS inthe two groups. The study by Laurent was the only ex-ception, reporting a higher 3-year survival for MIH(89% versus 55%); however this difference disappearedwhen excluding from survival analysis the two postop-erative deaths in the OH group [6].

Like any meta-analysis, our study is limited by thequality of studies included. Some degrees of selectionbias were apparent in most of the studies included in

our analysis. As mentioned above, for instance, twostudied only included subcapsular tumors in the MIHgroup. Moreover, despite measures taken to standard-ize surgical population and outcome definitions, varia-tions in inclusion criteria and operative techniquebetween studies might have lead to differences inoutcomes.

Funnel plots, constructed to assess for publicationbias, were symmetric for most of the outcomes and didnot suggest publication bias. In contrast, the funnelplots for mortality and overall complications had fewpositive studies of low precision. In usual cases of pub-lication bases, one would expect fewer negative trials oflow precision. It is possible themedical centers that per-form a larger volume of laparoscopic liver surgerieshave fewer complications than ‘‘low volume’’ centersdue to the steep learning curve for laparoscopic sur-gery. Further studies with a larger sample of medicalcenters will be needed to further confirm thispossibility.

A randomized controlled study of MIH versus OH forHCC would be required to overcome selection bias ofcurrently available databases, although we should rec-ognize that such a study would be unlikely to completeenrollment in an era when more and more patientsactively seek a minimally invasive approach for theiroperations, and more and more surgeons offerlaparoscopic liver surgery [9, 28, 33, 46, 50]. To ourknowledge, only one randomized controlled trialcomparing MIH and OH for HCC is under way, a studyfrom South Korea currently recruiting participants[51]. However, results from this trial may not withholdvalidity for the Western countries where HCC seems tobehave differently in terms of epidemiology and naturalhistory.

CONCLUSIONS

Although patient selectionmay have influenced someof the observed differences, our meta-analysis indicatesthat in carefully selected patients with HCC, MIHmight be associated with improved outcomes. Com-pared with OH, MIH appeared to decrease blood loss,blood transfusions, overall and specific morbidity, andhospital stay, while increasing rates of negative resec-tion margins. Overall and disease-free survival out-comes do not differ between MIH and OH, althoughfurther studies are needed to evaluate the impact ofMIH on long-term results.

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